HEARTLINE IRCCS San Martino Genoa Cardiology Meeting 15/16 Novembre 2013 Iperuricemia con o senza depositi di urato: inquadramento clinico e nuove strategie terapeutiche”, Giacomo Garibotto Università degli Studi di Genova IRCCS-AOU San Martino - IST “The viscera in time are so much injured, from the stagnation of the morbific matter therein, that the organs of secretion no longer perform their functions, whence the blood, overcharged with vitiated humours, stagnates, and the gouty matter ceases to be thrown upon the extremities as formerly, so that at length death frees him from his misery.” Thomas Sydenham, 1683 A Treatise of the Gout and the Dropsy TALBOTT JH, RERPLAN KL: The kidney in gout. Medicine 39:405—407, 1960 • ..there is an abundance of clinical and pathological data to implicate the kidney heavily in the pathogenesis of the most important complication. . . . Deposition of urate crystals may be followed by fibrosis as a sequel. • Laboratory evidence of renal involvement is a frequent finding in patients with gout. The development of renal insufficiency was critical in 18 per cent of the larger series and 25 per cent in the smaller series of postmortem protocols . Grantham JJ, Cuosno AM: The Kidney (3rd ed),BRENNER BM, RECTOR Ft. I'hiladelphia, Saunders. 1986, pp 688—689 …gouty nephropathy is a chronic form of interstitial nephritis resulting from the prolonged deposition of sodium urate crystals in the renal parenchyma. The distinctive histologic features of gouty nephropathy are the presence of urate crystals in the medulla and the surrounding giant cell reaction… Cotran, Rubin, and Tolkoff-Rubin, Tubulointerstitial diseases, in The Kidney (3rd ed), BRENNER BM, RECTOR FC, Philadelphia, Saunders, 1986 -The very existence of chronic gouty nephropathy, i.e. a chronic nephropathy specifically caused by deposition of urate crystals in the kidney is controversial. -In summary, many factors may contribute to chronic nephropathy in a patient with gout….. Kidney International, Vol. 30 (1986), pp. 280—287 NEPHROLOGY FORUM Requiem for gouty nephropathy Principal discussant: LAURENCE H. BECK …there is merely an association of SUA with other risk factors, including hypertension, renal disease, elevated lipoprotein levels, and use of diuretic agents.. ANNI 80-90 • Grandi progressi nella terapia della nefropatia acuta da acido urico (acute tumor lysis) • Diverso approccio all’iperuricemia isolata: Scuola statunitense: trattare uricemia solo se sintomatica o > 12 mg/dl Scuola europea: Trattare uricemia se > 6.8 mg/dl • pKa 5,75 nel sangue e 5,25 nelle urine Paulev Human Physiology Hyperuricemia= volume depletion + reduced secretion of uric acid. (also) genetically influenced The Hyperuricemia Cascade Dietary Purines Endogenous Purine Synthesis Tissue Nucleic acids Urate Underescretion Hyperuricemia Urate deposition Gout, renal calculi Acute renal failure (acute tumor lysis) Damage without urate deposition Acceleration of CKD ? Hypertension, CV disease Liver sinusoids cerebellum brain Urate deposition and inflammation in Acute Tumor lung Lysis kidney J Clin Hypertens 2006 Sindrome Metabolica Obesità Mean SUA levels have risen from 1920 Fishberg, Arch Int Med 1920s 1924; Afro3.40 Americani Hall, AmJ Med 1967; 1950s Acido Urico Insulino Resistenza 5.00 Diuretici Nefropatia Ipertensione Glynn, Arthritis Rheum 1970s 1983; 6.25 Uric acid mg/dl Metanalisi:l’aumento di 1 mg/dl di uricemia è associato ad aumento del: • 13% del rischio di ipertensione (Grayson 2011) • 16% di malattia coronarica (Kim 2011) • 13% di stroke (Kim 2012) • 17 % di sviluppo di diabete (Kodama 2012) Hazard Risk* (CI) 1.6 1.5 (1.1-1.9) 1.4 1.4 (1.1-1.8) 1.4 (1.1-1.8) 1.2 1.0 p=0.003 p= 0.006 p=0.004 0 Creatinine HOMA SUA 207 never treated hypertensive patients *also in model CRP, age, gender, DBP, lipid profile, smoking habits Modified from Zoccali C, et al. JASN 2006 Relationship of selected variables to the SUA and endotelial dysfunction in humans presence of endothelial dysfunction New onset diabetes on the basis of serum uric acid levels in primary hypertension NOD free survival , % 1 ,98 ,96 ,94 AU -, n=609 ,92 ,9 ,88 ,86 AU+, n=149 ,84 P <0.0001 (log-rank test) HR 20.21 ,82 0 2 4 6 8 10 12 14 16 years Viazzi F et al., Diabetes Care, 2011 SUA as a cardiovascular risk factor: a stronger association in women -LIFE studyHR for CV end point per 0.17 mg/dL 0.5 95% CI 1 1.5 All, SUA P<0.0001 All, adj SUA P= 0.09 women, SUA P<0.0001 women, adj SUA P= 0.03 men, SUA P 0.065 men, adj SUA P=0.41 Kidney Int, 65:1041-1049; 2004 Iperuricemia ? Danno vascolare, renale Cosa sono i radicali liberi? • Superoxide radical: O2 + eO2 • Protonation of O2 HO2 • Hydroxyl radical: H2O2 + Fe2+ OH+OH - + Fe3+ Activated mononuclear cells release NADPH oxidase Activated destruction of invaders O2 H2O2 NO, HOCl Bacteria NADPH oxidase 2O2 + NADPH 2O2 + NADP+ + H+ Extracellular Intracellular (Griendling Circ Res 2000) Human vascular smooth muscle cells express a urate transporter URAT 1 MAP Kinasi NFB AP1 COX2 Uric Acid TxA2 PDGF VSMC Proliferation Price KL et al, JASN 2006 MCP-1 Macrophage Infiltration A Model of Mild Hyperuricemia Uricase inhibitor Oxonic acid (OA) Normal Rat SUA (0.5-1.4 mg/dl) Hyperuricemic Rat SUA (1.7-3.0 mg/dl) Hyperuricemia induces arteriolosclerosis in a BP independent fashion Normal rat Hyperuricem ic rat Essential hypertension Mazzali et al, AJP Renal Physiol, 2002 Losartan Urat-1 inhibition SGLT-2 inhibition ( mg Dapagliflozin dose mg/dl decrease Reducing SUA is associated with beneficial effect on cardiac and renal outcomes - RENAAL study 5% risk reduction in CV morbidity and mortality per 0.5 mg/dL SUA decrement P<0.017 6% risk reduction per 0.5 mg/dL SUA decrement corrected for baseline and change in other risk markers 9.5 12.3 14.3 J Hypertens 2012 Allopurinol Febuxostat Losartan Urat -1 inibitori SGLT-2 inibitori Hare J M , Johnson R J Circulation 2003;107:1951-1953 Purine metabolism. Allopurinol and mortality in hyperuricaemic patients 9924 veterans with SUA> 7.0 mg/dl, 98% males, 88% white, mean age 62.7 years, 23903 person-years of f-up Δ SUA f-up 2483 in the allopurinol group (83% gout diagnosis) 7441 in the control group (20% gout diagnosis) adj for basal levels =0.68 mg/dL 25% AJ Luk et al. Rheumatology 2009 Effect of allopurinol on mortality and hospitalisations in CHF: a retrospective cohort study All cause mortality Struthers AD et al. Heart 2002;87:229–234 Allopurinol Slows the Progression of Renal Disease Through Its Ability to Lower SUA Level SUA levels significantly decreased in subjects treated with allopurinol, from 9.75±1.18 mg/dL to 5.88±1.01 mg/dL (P < 0.001). Siu YP et al. Am J Kidney Dis 47:51-59 Does reducing SUA slows the progression of renal disease? Allopurinol group, n=57 Control group, n= 56 24 mos F-up 0,5 allopurinol reduces CVE (71%) and hospitalization risk (60%) P= 0.0180 P<0.0001 2 0 1 -0,5 0 -1 -1 -1,5 -2 -2 -3 Uric acid change (mg/dl) -4 eGFR change (ml/min/1.73m2) Control group HR 1.88 accelerated progression adj for age, gender, diabetes, UA, hs-CRP, albuminuria, CKD etiology, RAS blockers Goicoechea M et al; CJASN 2010 Impact of allopurinol dose on CV outcome Li Wei, Br J Clin Pharmac 2011 300 mg vs 100 mg adj HR 0.75 95% CI 0.59– 0.94 7137 patients aged 60 year 1035 allopurinol users Effects of Urate-Lowering Therapy in Hyperuricemia on Slowing the Progression of Renal Function: A Meta-Analysis Wang H, et al, J Ren Nutr. 2012 Allopurinolo inibisce solo la forma ridotta Ipoxantin a Febuxostat XANTINA OSSIDASI Forma ridotta Xantin a XANTINA OSSIDASI Forma ossidata Acido Urico XANTINA OSSIDASI Forma ridotta XANTINA OSSIDASI Forma ossidata inibisce forma ridotta e ossidata Febuxosta t Febuxosta t Febuxostat Compared with Allopurinol in Patients with Hyperuricemia and Gout: FACT study % of patients with SUAconcentration of less than 6.0 mg per deciliter (360 μmol per liter) at the last three monthly measurements 762 patients with gout and with serum urate concentrations of at least 8.0 mg per deciliter. The primary end point was a serum urate concentration of less than 6.0 mg per deciliter at the last three monthly measurements 80 70 60 50 * 53% * 62% *p < 0.001 vs allopurinol 40 30 21% 20 10 0 Febuxostat 80 mg (n=255) Febuxostat 120 mg (n=250) Allopurinol 300 mg (n=251) Becker MA, et al. N Eng J Med 2005 Allopurinol- and Placebo-Controlled, Efficacy Study of Febuxostat: APEX study Subjects (n =1.072) with serum urate level >8.0 mg/dL and gout and normal or impaired RF (creat. >1.5 to <2.0 mg/dl) 80 – Proportion of patients (%) 70 – 60 – 50 – 40 – Patients with Normal Renal Function Patients with Impaired Renal Functio 175/269 ᵃ ᵇ 170/258 126/262 ᵃ ᵇ ᶜ 122/153 5/11 4/9 • Ten patients received 100 mg and 258 subjects received 300 mg of allopurinol based on renal function. a = p < 0.05 versus allopurinol in patients with impaired renal function; b = p < 0.001 versus allopurinol in all patients; c = p < 0.001 versus febuxostat 120 mg in all patients. 60/268 30 – 60/258 20 – 10 – 0/10 Febuxostat 120 mg (n=269) _ Febuxostat 80 mg (n=262) _ _ 0– Allopurinol 300 mg * (n=268) Becker MA et al. Arthritis Research & Therapy 2010; 12: R63. Febuxostat vs Allopurinol: And the Winner Is... At the doses tested, safety of febuxostat and allopurinol was comparable. Creatininemia >1.5-<2.0 mg/dl) 100 80 Pazienti (%) 2,269 subjects with gout and serum urate (sUA) ≥ 8.0 mg/dL in a six-month trial Urate-lowering efficacy of febuxostat 80 mg exceeded that of febuxostat 40 mg and allopurinol (300/200 mg), which were comparable. In subjects with mild/moderate renal impairment (65%), both febuxostat doses were more efficacious than allopurinol and equally safe. 71,6 % 60 p<0.001 42,3 % 40 20 0 Febuxostat 80 mg (n=360/503) Allopurinolo 200 mg (n=212/501) Effect of febuxostat on renal function and CV damage in cardiac surgery patients NU-FLASH Trial Cardiac surgery patients with hyperuricemia (n=141) were randomized to or allopurinol Sezai A, Circ J; in press 2013 • Molti studi indicano che livelli aumentati di acido urico costituiscono un fattore predittivo di ipertensione, eventi cardiovascolari e renali • L’acido urico sembra essere implicato nelle fasi precoci del danno cardiorenale • Dati su casistiche meno estese indicano che la riduzione dell’uricemia conferisce protezione renale e cardiovascolare • Il nuovo inibitore delle xantine ossidasi febuxostat è più potente e tollerabile rispetto all’allopurinolo. The purine degradation pathway Allopurinol Febuxostat Berry CE et al. J Physiol. 2004; 555(Pt 3):589–606.1 Iperuricemia > 6.0 mg/dl • Iperproduzione • Dieta alcool • Elevato turnover cellulare e chemioterapia • Disturbi genetici (rari) • • • • • • • • Iposecrezione Genetica CKD Insulino resistenza Ipertensione Diuretici tiazidici o d’ansa Ciclosporina Aspirina (piccole dosi) HTN patients with LVH and hyperuricemia have an increased risk of developing CVD Probability of event-free survival (%) 100 Lower LVMI and UA Lower LVMI and higher UA 90 Higher LVMI and lower UA Log-rank χ2 13.2; P<0.004 80 70 Higher LVMI and UA Adj. incidence of CVD in patients with 0 15 30 was 2.4 fold higher than in 45 60 75 Time to event (months) N=619 HTN patients free of prior CVD Iwashima Y et al. Hypertension 2006. Reducing SUA is associated with beneficial effect on CV outcomes - LIFE study 400 6.7 P< 0.0001 SUA, mg/dL 6.3 375 5.9 350 5.5 325 5.0 300 4.6 275 0 anni 1 Overall= 9193 Kidney Int, 65:1041-1049; 2004 2 3 Losartan 4 Atenololo 5 6 Reducing SUA is associated with beneficial effect on cardiac outcomes - RENAAL study 5% risk reduction in CV morbidity and mortality per 0.5 mg/dL SUA decrement P<0.017 12% risk reduction in hospitalization for HF per 0.5 mg/dL SUA decrement P<0.001 J Hypertens 2012 Diuretic – related increase in SUA partially offset the treatment benefit SHEP study Treatment group after 1 year disease Coronary heart HR Placebo, SUA increase < 1 mg/dl (n=1543) may 95% CI 1 Placebo, SUA increase ≥ 1 mg/dl (n=296) 1.08 0.63-1.83 Chlorthalidone, SUA increase < 1 mg/dl (n=985) 0.56 0.37-0.85* Chlorthalidone, SUA increase ≥ 1 mg/dl (n=942) 0.96 0.67-1.39 from Franse LV et al, J Hypertens, 2000 148.217 patients, mean eGFR 84 ml/min/1.73m2, CKD stages III-IV 6%, UA>7 mg/dl 15.6% Mean follow-up 1.26 ±0.95 yrs CV morbidity: MI, subacute CHD, HF, cerebrovascular disease or peripheral arterial disease 33% in UA in pts with UA >5.7 mg/dl ↓6.1% in nonCKD or stages 1-2 9.4% in CVE ↓60.2% in stages 3-5